Insulin resistance and type 2 diabetes are important risk factors for heart disease. Insulin resistance accompanies all patients who become obese, and progressive insulin resistance leads to type 2 diabetes in susceptible subjects. Yet the mechanisms interrelating obesity, insulin resistance, and type 2 diabetes are not well understood. For example, about 1/3 of normal individuals gain minimal weight when overfed, suggesting a defense against obesity. Similarly, insulin resistance develops to varying degrees with increased adiposity: about 20% of patients with type 2 diabetes are lean, and many obese subjects never develop diabetes and remain relatively sensitive to insulin. Although the mechanism of obesity-related insulin resistance is unclear, the public health implications are enormous because of the increasing incidence of obesity in the American population. We have preliminary data that demonstrate a consistent increase in capillary/fiber ratio, and an increase in muscle fiber oxidative capacity, with weight loss, even though there was no change in the proportion of oxidative or glycolytic muscle fibers. We will further examine the relationship between muscle oxidative capacity and insulin resistance, and link these findings to our other studies of TNFa and UCP expression.